Inhibition of DNA polymerase α by gossypol

Rosenberg, Larry; Adlakha, Ramesh C.; Desai, Devdatta M.; Rao, Potu N.

doi:10.1016/0167-4781(86)90051-5

Cited by 29 publications

(8 citation statements)

References 28 publications

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“…Cottonseed meal containing high content of gossypol has been reported to cause fatal poisoning in livestock (Haschek et al 1989;Morgan 1989). Although the exact mechanism of toxic action of gossypol is not fully understood, experimental studies have shown that it chelates with iron (Morgan 1989), inhibits key enzymes involved in cellular respiration in mitochondria (Abou-Donia & Dieckert 1974), co-valently binds to microsomal membranes (Moh et al 1992) and shows inhibitory effect on DNA synthesis (Rosenberg et al 1986;Zaidi & Hadi 1992). Since liver is one of the major target organs for gossypol toxicity, the present studies were conducted to examine the effect of gossypol administered alone and with phenobarbital on the liver and liver biotransformation enzymes in rats.…”

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confidence: 99%

Changes in the Activity of Metabolic and Non‐Metabolic Liver Enzymes in Rats Following Co‐Administration of Gossypol with Phenobarbital

Gawai

Cox

Jackson

et al. 1995

Pharmacology & Toxicology

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confidence: 99%

Changes in the Activity of Metabolic and Non‐Metabolic Liver Enzymes in Rats Following Co‐Administration of Gossypol with Phenobarbital

Gawai

Cox

Jackson

et al. 1995

Pharmacology & Toxicology

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“…Early studies in HeLa cells demonstrated that the cytotoxicity of gossypol was based on its inhibitory activity on DNA synthesis through DNA polymerases alpha and beta 12 or on topoisomerases. 13 Gossypol's effect on DNA synthesis, leading to S-phase arrest, was specific: no effects on RNA and protein syntheses were observed.…”

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confidence: 99%

Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells

Balakrishnan¹,

Wierda

Keating

et al. 2008

Blood

117

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Gossypol, a cottonseed extract derivative, acts as a BH3-mimetic, binding to the BH3 pocket of antiapoptotic proteins and displacing pro-death partners to induce apoptosis. However, knowledge on the molecular underpinnings of its downstream effects is limited. Since chronic lymphocytic leukemia (CLL) cells express high levels of antiapoptotic proteins that act as a survival mechanism for these replicationally quiescent lymphocytes, we investigated whether gossypol induces apoptosis in these cells and what mechanism underlies gossypol-mediated cytotoxicity. Gossypol induced cell death in a concentration-and time-dependent manner; 24-hour incubation with 30 M gossypol resulted in 50% cell death (median; range, 10%-80%; n ‫؍‬ 47) that was not abrogated by pan-specific caspase inhibitor. Starting at 4 hours, the mitochondrial outer membrane was significantly permeabilized (median, 77%; range, 54%-93%; n ‫؍‬ 15). Mitochondrial outer membrane permeabiliztaion (MOMP) was concurrent with increased production of reactive oxygen species (ROS); however, antioxidants did not abrogate gossypolinduced cell death. Mitochondrial membrane permeabilization was also associated with loss of intracellular adenosine triphosphate (ATP), activation of BAX, and release of cytochrome c and apoptosisinducing factor (AIF), which was translocated to the nucleus. Blocking AIF translocation resulted in a decreased apoptosis, suggesting that AIF contributes to gossypol-mediated cytotoxicity in CLL lymphocytes. (Blood. 2008;112:1971-1980 Introduction Gossypol, a natural product derived from cottonseed extracts, was originally extensively investigated in China as a male contraceptive agent. 1 It exhibits a type of enantiomerism that arises from restricted rotation: the (Ϫ)-gossypol isomer showed greater cytotoxicity than the (ϩ)-isomer in several human cancer cell lines. 2 To reduce toxicity, structural modifications in the (Ϫ)-gossypol isomer led to the analog apogossypol, which lacks the reactive aldehydic groups and displays proapoptotic activity comparable with that of gossypol 3 ; another derivative, gossypolone, demonstrates lower cytotoxicity than the parent compound. 4 The success of these agents resulted in the development of additional analogs, such as the l-isomer of gossypol, AT-101, 5 and ABT-737, which was designed on the basis of structure activity-based studies. 6,7 The gossypol isomers and analogs exhibited inhibitory activity against a wide range of human carcinoma cell lines and in tumor xenograft models. [8][9][10][11] However, these and other investigations illustrated different actions of this agent, and knowledge on the molecular underpinnings of its biologic effects is still limited.Early studies in HeLa cells demonstrated that the cytotoxicity of gossypol was based on its inhibitory activity on DNA synthesis through DNA polymerases alpha and beta 12 or on topoisomerases. 13 Gossypol's effect on DNA synthesis, leading to S-phase arrest, was specific: no effects on RNA and protein syntheses were observed. 14 In concordance...

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“…Numerous biochemical studies have been conducted to elucidate the mechanisms by which gossypol exerts its antiproliferative effects (Rosenberg et al, 1986;Adlakha et al, 1989). Data are limited and understanding of gossypol's influence on cell cycle control of DNA synthesis and antimitogenic activity is incomplete (Wang and Rao, 1984; Thomas et al, 1991).…”

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confidence: 99%

Gossypol inhibition of mitosis, cyclin D1 and Rb protein in human mammary cancer cells and cyclin-D1 transfected human fibrosarcoma cells

Ligueros

Jeoung²,

Tang³

et al. 1997

Br J Cancer

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Summary The antiproliferative effects of gossypol on human MCF-7 mammary cancer cells and cyclin Dl-transfected HT-1060 human fibrosarcoma cells were investigated by cell cycle analysis and effects on the cell cycle regulatory proteins Rb and cyclin Dl. Flow cytometry of MCF-7 cells at 24 h indicated that 10 gm gossypol inhibited DNA synthesis by producing a G,/S block. Western blot analysis using antihuman Rb antibodies and anti-human cyclin Dl antibodies in MCF-7 cells and high-and low-expression cyclin Dl-transfected fibrosarcoma cells indicated that, after 6 h exposure, gossypol decreased the expression levels of these proteins in a dose-dependent manner. Gossypol also decreased the ratio of phosphorylated to unphosphorylated Rb protein in human mammary cancer and fibrosarcoma cell lines. Gossypol (10 gM) treated also decreased cyclin D1-associated kinase activity on histone Hi used as a substrate in MCF-7 cells. These results suggest that gossypol might suppress growth by modulating the expression of cell cycle regulatory proteins Rb and cyclin Dl and the phosphorylation of Rb protein.

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Inhibition of DNA polymerase α by gossypol

Cited by 29 publications

References 28 publications

Changes in the Activity of Metabolic and Non‐Metabolic Liver Enzymes in Rats Following Co‐Administration of Gossypol with Phenobarbital

Changes in the Activity of Metabolic and Non‐Metabolic Liver Enzymes in Rats Following Co‐Administration of Gossypol with Phenobarbital

Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells

Gossypol inhibition of mitosis, cyclin D1 and Rb protein in human mammary cancer cells and cyclin-D1 transfected human fibrosarcoma cells

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